SHORT COMMUNICATION: Phenobarbital selectively promotes initiated cells with reduced TGFβ receptor levels

Phenobarbital (PB) is a potent tumor promoter in rodentliver. In this study we investigated whether PB selectivelypromotes a population of initiated cells with reduced levelsof transforming growth factor-P (TGFP) receptors types I,II and III. Liver tumors were induced in male Fischer F344rats by diethylnitrosamine (DEN). Following inductionthe animals were divided into PB-treated (DEN/PB) anduntreated groups (DEN). After 3 months of treatment halfof the PB-treated rats were removed from PB for the finalmonth (DEN/PB/OFF). At 4 months, the livers from ratsin the three treatment groups were removed, tumors excisedand frozen with matched surrounding normal tissue. ThemRNA levels for the TGFp receptors types I-HI weresignificantly decreased in tumor tissue from DEN/PB ratswhen compared with surrounding normal liver tissue ortumors from age-matched untreated controls. In tumorsfrom DEN/PB/OFF rats the TGFp receptor types I-mwere also significantly reduced compared with controls andnot different to tumors from DEN/PB rats. There was nodifference in the mRNA levels for the TGFP receptors intumors from rats exposed to DEN alone, when comparedwith the surrounding normal tissue. These results demon-strate that PB selectively promotes initiated cells withreduced levels of TGFP types I-HI receptors and suggestsa mechanistic role for TGFp in PB-induced liver tumorpromotion.Approximately 60% of the chemicals determined by theNational Toxicology Program to be carcinogenic in rats andmice give rise to liver tumors. Some of these carcinogens,however, are either only weakly genotoxic or have been foundto cause no detectable genetic damage. Rather, they appear tofunction as tumor promoting agents. These agents includechemicals to which humans are exposed, e.g. contraceptivesteroids (1,2), tamoxifen (3), benzodiazepine compounds (4),dioxin (5), and phenobarbital (PB*) (6). Although there is nodefinitive mechanism for the carcinogenic activity of thesediverse agents, one hypothesis involves reduced reponsivenessto negative growth signals, especially the potent mitoinhibitortransforming growth factor-P (TGFP) (7).In mammals TGFP exists as three highly homologousisoforms, TGFpi, TGFP2 and TGFP3 (8). These structurally

[1]  M. Andersen,et al.  Negative selection in hepatic tumor promotion in relation to cancer risk assessment. , 1995, Toxicology.

[2]  R. Jirtle,et al.  Induction of apoptosis in liver tumors by the monoterpene perillyl alcohol. , 1995, Cancer research.

[3]  R. Jirtle,et al.  Mechanisms of liver tumor promotion , 1995 .

[4]  R. Jirtle,et al.  Transforming growth factor-beta receptors type I, II and III in phenobarbital-promoted rat liver tumors. , 1994, Carcinogenesis.

[5]  M. Tsao,et al.  Transforming Growth Factor β1 Promotes Spontaneous Transformation of Cultured Rat Liver Epithelial Cells , 1994 .

[6]  Jeffrey L. Wrana,et al.  Mechanism of activation of the TGF-β receptor , 1994, Nature.

[7]  R. Jirtle,et al.  Regulation of mannose 6-phosphate/insulin-like growth factor-II receptors and transforming growth factor beta during liver tumor promotion with phenobarbital. , 1994, Carcinogenesis.

[8]  M. L. Gustafson,et al.  A transforming growth factor beta type I receptor that signals to activate gene expression. , 1994, Science.

[9]  W. Bursch,et al.  Cell proliferation and apoptosis in normal liver and preneoplastic foci. , 1993, Environmental health perspectives.

[10]  J. Massagué,et al.  Betaglycan presents ligand to the TGFβ signaling receptor , 1993, Cell.

[11]  H. Lodish,et al.  Growth inhibition by transforming growth factor beta (TGF-beta) type I is restored in TGF-beta-resistant hepatoma cells after expression of TGF-beta receptor type II cDNA. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[12]  G. Williams,et al.  The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat. , 1993, Carcinogenesis.

[13]  R. Weinberg,et al.  Expression cloning of the TGF-β type II receptor, a functional transmembrane serine/threonine kinase , 1992, Cell.

[14]  M. Laiho,et al.  Transforming growth factors-beta as regulators of cellular growth and phenotype. , 1992, Critical reviews in oncogenesis.

[15]  R. Jirtle,et al.  Modulation of insulin-like growth factor-II/mannose 6-phosphate receptors and transforming growth factor-beta 1 during liver regeneration. , 1991, The Journal of biological chemistry.

[16]  R. Weinberg,et al.  Expression cloning and characterization of the TGF-β type III receptor , 1991, Cell.

[17]  D. Rifkin,et al.  Cellular activation of latent transforming growth factor beta requires binding to the cation-independent mannose 6-phosphate/insulin-like growth factor type II receptor. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[18]  K. Miyazono,et al.  TGF-β1 binding protein: A component of the large latent complex of TGF-β1 with multiple repeat sequences , 1990, Cell.

[19]  H. Moses,et al.  Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin , 1990, The Journal of cell biology.

[20]  M. Danhof,et al.  Pharmacokinetic modeling of the anticonvulsant action of phenobarbital in rats. , 1989, The Journal of pharmacology and experimental therapeutics.

[21]  K. Miyazono,et al.  Interactions of recombinant and platelet transforming growth factor-beta 1 precursor with the insulin-like growth factor II/mannose 6-phosphate receptor. , 1989, Biochemical and biophysical research communications.

[22]  R. Coffey,et al.  Type beta transforming growth factor reversibly inhibits the early proliferative response to partial hepatectomy in the rat. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[23]  R. Weinberg,et al.  Absence of TGF-beta receptors and growth inhibitory responses in retinoblastoma cells. , 1988, Science.

[24]  M. Sporn,et al.  Transforming growth factor beta. , 1988, Advances in cancer research.

[25]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[26]  S. Thorgeirsson,et al.  Differential effects of transforming growth factor-beta on proliferation of normal and malignant rat liver epithelial cells in culture. , 1986, Cancer research.

[27]  H. Moses,et al.  Inhibition of DNA Synthesis in rat hepatocytes by Platelet-derived Type β Transforming Growth Factor , 1986 .

[28]  T. Nakamura,et al.  Inhibitory effect of transforming growth factor-beta on DNA synthesis of adult rat hepatocytes in primary culture. , 1985, Biochemical and biophysical research communications.

[29]  J. Yager,et al.  Oral contraceptive steroids as promoters of hepatocarcinogenesis in female Sprague-Dawley rats. , 1980, Cancer research.

[30]  H. Pitot,et al.  Quantitative evaluation of the promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxin of hepatocarcinogenesis from diethylnitrosamine. , 1980, Cancer research.

[31]  J. Baum,et al.  Possible association between benign hepatomas and oral contraceptives. , 1973, Lancet.

[32]  E. Staffeldt,et al.  Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. , 1971, Cancer research.